Therapeutic use of steroidal hormones is required in the treatment of a number of diseases, including lack of natural hormones, osteoporosis, and premenstrual syndrome. However, effective treatment is difficult, since these steroids are absorbed only slowly from the gastrointestinal tract, and are rapidly cleared from circulating blood by the liver.
Numerous attempts have been made to circumvent these problems, including the administration of huge doses of natural hormones orally or preparations of oil solutions of hormones which are injected intramuscularly, and synthesis of analogs of natural hormones. The latter approach provides active preparations which may have significant side effects. Administration of these hormones transdermally or by nasal sprays has also been suggested, but these methods have not met with great acceptance. The optimal method for the administration of steroidal hormones would use noninvasive entry of physiological amounts of chemically unmodified hormones, and would lead to normal levels of hormones in the circulation. Furthermore, such a method should be adaptable for mass use.
Deficiency of steroidal hormones in the elderly is a problem of particularly serious consequences. In postmenopausal women, unless corrected, this deficiency leads to osteoporosis, which, in the United States, is blamed for over one million bone fractures annually. In men, the production of testosterone does not dramatically decrease with age, but the amount of testosterone binding globulin increases and thus, in some men, hormonal supplementation is needed.
Steroidal hormones are readily available, and supplementation by natural compounds can be used. However, oral administration of these steroids is complicated by their lack of solubility, which delays their absorption until they reach the lower gastrointestinal tract, where metabolism by the portal vein-liver system, i.e., first-pass effect, and degradation by microbial flora are problems.
The use of hydrophilic cyclodextrin derivatives in pharmaceutical preparations of steroid hormones has been disclosed in Pitha, U.S. Pat. No. 4,596,795. Amorphous hydrophilic derivatives of beta- and gamma-cyclodextrins seemed to give better results than any of the parent cyclodextrins for the solubilization of steroid hormones, a step which appears to be crucial for their absorption by tissues. In a human trial, amorphous derivatives of beta-cyclodextrins enabled effective administration of testosterone, estradiol, or progesterone under conditions when improvements obtainable with beta-cyclodextrin alone were marginal.
Hayashi et al., in British application No. 2,104,907A, disclose cyclodextrin inclusion compounds wherein at least one guest compound selected from the group consisting of eicosapentaenoic acid and docosahexaenoic acid is included. The guest compound reduces cholesterol levels in human serum, and the inclusion compound can be incorporated for this purpose in pharmaceutical compositions.
Jones, in U.S. Pat. No. 4,555,504, disclose inclusion compounds of cyclodextrins and cardiac glycosides which have high aqueous solubility and can be used for preparing pharmaceutical formulations containing cardiac glycosides for use in therapy. The preferred cyclodextrin is beta-cyclodextrin.
Szejtli et al., in U.S. Pat. No. 4,524,068, disclose a cyclodextrin inclusion complex of piperonyl butoxide. In this case, the complex is prepared by reacting cyclodextrin or an aqueous or non-aqueous solution thereof with piperonyl butoxide. The cyclodextrin complexes are said to synergize the pesticidal effect of known insecticides and fungicides to a greater extent than piperonyl butoxide.
Szejtli et al., in U.S. Pat. No. 4,380,626, disclose inclusion compounds of 2-chloro ethyl phosphonic acid formed with an alpha-, beta-, or gamma-cyclodextrin or mixtures thereof. These complexes can be used for preparing plant growth regulating compositions.
Pitha et al., in J. Pharm. Sci. 75, No. 2, February, 1986, 165-167, disclose that condensation products of beta-cyclodextrin with propylene oxide or epichlorohydrin, which are amorphous and thus very soluble in water, can be used to form complexes with testosterone, progesterone, and estradiol.
Cyclodextrins are products of the enzymatic degradation of starch, and contain six to eight glucose units joined in a ring by alpha-1.fwdarw.4 glycosidic bonds. They are known to solubilize nonpolar compounds and improve the absorption of drugs from the gastrointestinal tract. Nevertheless, beta-cyclodextrin itself has proven unsuitable for improving the absorption of drugs.
The lack of toxicity of the cyclodextrins has already been documented using animals.
It has been observed that steroidal hormones are present in the serum only when the drug is absorbed into the bloodstream in such a means that the portal vein is bypassed. This is in accordance with the fast metabolism of steroidal hormones in the liver. The half-lives of these hormones in the circulatory system are estimated to be in minutes. The direct route into the bloodstream bypassing the portal vein is known to be less immediately affected by liver metabolism than entry from the gastrointestinal tract. Furthermore, metabolism of the drug by intestinal tissue is avoided.